Epigenetic Regulation of G6PD Drives Metabolic Reprogramming in Intrahepatic Cholangiocarcinoma

Area of Science:

• Oncology
• Molecular Biology
• Epigenetics

Background:

• Intrahepatic cholangiocarcinoma (ICC) is an aggressive liver cancer with poor outcomes.
• Metabolic reprogramming is a hallmark of cancer, but its drivers in ICC are not fully understood.
• The pentose phosphate pathway (PPP) and its key enzyme G6PD are implicated in cancer metabolism.

Purpose of the Study:

• To investigate the role of tumor-specific enhancers in regulating metabolic reprogramming in ICC.
• To elucidate the function of G6PD and the PPP in ICC progression and chemoresistance.
• To identify potential therapeutic targets within enhancer-mediated regulatory networks.

Main Methods:

• Native elongating transcript-cap analysis of gene expression (NET-seq) and single-cell RNA sequencing were employed.
• Functional assays were conducted to assess the impact of G6PD on ICC cell proliferation and redox homeostasis.
• Enhancer knockdown experiments were performed to evaluate the effects on G6PD expression and PPP activity.
• Survival analyses were performed on ICC patient data.

Main Results:

• Tumor-specific enhancers driving G6PD overexpression were identified in ICC epithelial cells.
• G6PD enhances ICC proliferation by boosting PPP activity, maintaining redox balance, and supplying NADPH.
• Enhancer knockdown reduced G6PD and PPP activity, increased reactive oxygen species, and decreased the NADPH/NADP+ ratio.
• High G6PD expression correlated with poor overall survival in ICC patients.
• Targeting G6PD sensitized ICC cells to cisplatin, indicating potential for overcoming chemoresistance.

Conclusions:

• Tumor-specific enhancers are critical epigenetic drivers of metabolic reprogramming and progression in ICC.
• G6PD-mediated PPP activation is crucial for ICC cell proliferation, redox homeostasis, and chemoresistance.
• Targeting G6PD and its regulatory enhancers presents a promising therapeutic strategy for ICC.
• Further research into enhancer profiling and targeting could advance precision medicine for ICC.